Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-05-28
1999-10-05
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 2, 514 11, 514 14, 514 15, 514 17, 530330, 530325, 530326, 530327, 530328, 530329, 530317, C07K 706, C07K 708, A61K 3702
Patent
active
059624183
DESCRIPTION:
BRIEF SUMMARY
The present invention is concerned with peptide reagents and compositions thereof which reduce blood clot formation.
Blood clotting relies upon a series or cascade of activating reactions to produce the ultimate fibrin clot. The cascade leading to fibrin formation may be triggered initially in two different ways--by contact with abnormal surfaces (the "intrinsic pathway") or by traumatization of blood vessels which causes secretion of the lipoprotein known as "tissue factor" or TF (the "extrinsic pathway"). The present invention is primarily concerned with the extrinsic blood clotting pathway.
TF is an integral membrane protein which appears on many cell types. However, cells which constitutively express TF, for example the muscle cells of vessels intima, are not normally exposed to blood (see Edgington et al., Thromb. Haemostas. 66(1): 67-69 (1991)). Thus initiation of the extrinsic blood clotting pathway appears to require either the disruption of blood vessel walls (see Almus et al., Blood 76: 354-360 (1990)) and/or activation of endothelial cells or monocytes to express TF (see Edwards et al., Blood ii: 359-370 (1979) and Bevilaqua et al., PNAS USA Da: 4533-4537 (1986)). Disruption of the blood vessel wall may occur due to fissuring of an atherosclerotic plaque which exposes tissue macrophages and smooth muscle cells to the blood (see Wilcox et al., PNAS USA 86: 2839-2843 (1989)). TF may also be exposed following injury to blood vessels during thrombolytic therapy, surgery for grafting, mechanical restoration of vessel patency or other similar techniques. On the other hand, TF expression in endothelial cells or in monocytes may be induced during sepsis due to production of tumour necrosis factor-.alpha. or interleukin-1 (see Edwards et al., supra and Gregory et al., J. Clin. Invest. 76: 2440-2445 (1985)).
The serine protease Factor VIIa (FVIIa) is involved in the extrinsic blood clotting pathway. FVIIa is formed by proteolysis from its inactive pro-enzyme Factor VII (FVII) by other participants in the blood clotting process, including Factor Xa, Factor XIIa, Factor IXa or thrombin. Activation of FVII to FVIIa has been reported to be markedly enhanced when FVII is bound to its co-factor tissue factor (TF) (see Nemerson, Semin. Hematol. 29(3): 170-176 (1992)). Yamamoto et al. have also suggested that conversion of FVII to FVIIa may be autocatalytic (see J. Biol. Chem. 267(27): 19089-19094 (1992)).
FVIIa forms a complex with TF in the presence of calcium ions and the FVIIa/TF complex catalyses the conversion of Factor X to its active form, Factor Xa, in the next step of the blood clotting process via the extrinsic pathway.
The structure of FVII has been investigated and the cDNA sequence was reported by Hagen et al. in PNAS USA 83: 2412-2416 (1986). FVII is a vitamin K dependent protein and, by analogy to other vitamin K dependent proteins, a putative .gamma.-carboxyglutamic acid (Gla) domain has been identified at the amino terminal. It was predicted, again by analogy to the other vitamin K proteins, that the Gla domain was required for binding to TF (see Hagen et al., supra). The Gla domain is followed by two potential growth factor (GF) domains. However, the literature has not suggested any function for the GF domains.
Activation of the extrinsic pathway for blood clot formation has been suggested as the primary event leading to fibrin formation (see Weiss et al., Blood 71: 629-635 (1988) and Weiss et al., Blood 73: 968-975 (1989)) and is thus of prime importance in the pathogenesis of arteriosclerotic lesions and in reocculusion and and restenosis following endarterectomy. However effective therapeutic agents able to intervene in the activation of this pathway are not available, despite demand (see Shepard, TIBTECH 9: 80-85 (1991)).
The present invention provides peptides and analogues or salts thereof which inhibit the association of FVII or FVIIa with TF. Through the action of the peptides according to the invention, formation of the FVIIa/TF complex is limited and therefore activation of Factor X i
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Rudinger, J `Characteristics of amino acids as components of peptide hormones sequence` in Peptide Hormones, (ed. J.A. Parsons). University Park Press, Baltimore, pp. 1-7, 1976.
Orning Lars
Sakariassen Kjell Steinar
Stephens Ross Wentworth
Gupta Anish
Nycomed Imaging A/S
Tsang Cecilia J.
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